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Revealing these hidden shapes has always been a means to understanding how the machines work, what they do. So Steitz dogs after a target for years, decades, capturing snapshots in the life of a protein. Frame by hard-earned frame, a movie appears. Molecular behaviors emerge. Actions make sense.
Early on, Steitz discovered he had a knack for making crystals—the fickle first step in the process of figuring out a molecule's shape. “Crystallography is a little bit of witchcraft—or maybe it's a lot of witchcraft,” says François Franceschi, a crystallographer at Rib-X Pharmaceuticals, the New Haven, Connecticut, company Steitz cofounded in 2001. When starting with an unmapped protein, a scientist doesn't know the conditions under which the particles will line up and solidify. The scientist doesn't even know if any given protein can make a crystal. The protein might be too floppy, too fragile, too this, too that. Superstitions abound: Maybe this lucky lab jacket will do it; maybe if I hop on one foot while stirring; maybe if I turn around three times and say a Hail Mary while tossing salt over my shoulder.
Though Steitz stopped his direct crystal wrangling in the late 1980s, he still takes pride in the skill. He recalls a Christmas break—he often works during breaks—late in his hands-on career, when a lab member was stymied. Steitz crystallized the stubborn protein and at the end of the week had “one and two millimeter monsters.” He left them in the lab with a note saying, “There it is.”
Around that time Steitz began eyeing the looming peak, the last in the line, the reason all those other shapes existed. There was a problem, though: Someone else, his Nobel colaureate, Yonath, had staked out the turf. In 1980, she made the first ribosome crystals. Among crystallographers, says Moore, there is a “courtesy convention that says you don't jump in on top of somebody who had crystallized something. You give them the opportunity” to use the pretty, hard-won specks to solve the structure themselves.
But the years ticked by, and Steitz grew antsy. He began planning to use Yonath's recipe as a jumping off point. “I've gotten some heat about that,” says Steitz. “In the crystallography field, they say, ‘Oh, those are Yonath's, right?’ But after 10 years, good grief.” There was no reason for Steitz to start from nothing— Yonath had published her work.
Franceschi, who collaborated with Yonath's lab for 12 years, says, “It was clear that at some point other people were going to jump on the train. But, I think at the end of the day, competition is what fuels progress.”
The Yale ribosome project launched in 1995 when an incoming postdoc named Nenad Ban agreed to take on the challenge. After a lot of noggin-scratching, Steitz, Ban, and Moore found a couple of possible reasons why Yonath was not succeeding: First, the crystals were hypersensitive to salt. A drop in salinity caused them to “twin.” The ribosome particles aligned in two distinct patterns instead of one. That slowed progress for a year or so until it was solved. The more challenging problem, however, was how to make a heavy atom derivative of these crystals and correctly locate the positions of the bound heavy atoms in the crystal. It required new approaches.